Androgen Receptor (AR) is a receptor which binds to ligands such as testosterone and dihydrotestosterone, and then translocates to the nucleus. There it acts as a DNA-binding transcription factor, regulating gene expression and many other functions.
Over-expression or mutation of AR has been implicated in various diseases, including cancer, including prostate cancer and many other diseases.
Prostate cancer is one of the most commonly diagnosed cancers in the world. Kawata et al. The Prostate 70, 745-754 (2010); and Jemal et al. CA 58, 71-96 (2008). Although localized tumors are often curative, distant metastases emerge in a significant fraction of patients. Scher et al. Journal of clinical oncology 23, 8253-8261 (2005); and Clegg et al. Cancer research 72, 1494-1503 (2012). Androgen-deprivation therapy, including surgical or chemical castration, is initially effective; however, resistance is almost always acquired that results in a much more aggressive form of tumor referred to as castration-resistant prostate cancer (CRPC). CRPC is the second most common cause of cancer-related deaths in American men [Jemal et al. CA: a cancer journal for clinicians 60, 277-300 (2010)] and is currently incurable. A conserved feature of CRPC is the sustained activity of AR-signaling [Chen et al. Nature medicine 10, 33-39 (2004)], by virtue of many mechanisms including AR gene overexpression/amplification and AR gene mutations. Scher et al. Journal of clinical oncology 23, 8253-8261 (2005). The continued reliance on AR signaling in CRPC led to the development of competitive inhibitors that compete with androgens for binding to the ligand-binding pocket of AR. Bicalutamide is such an anti-androgen that has been clinically used for many years as a monotherapy or in combination with castration to block androgen action. However, in the setting of CRPC, bicalutamide undergoes an antagonist-to-agonist switch, paradoxically enhancing AR signaling activity. Culig et al. British journal of cancer 81, 242-251 (1999).
Recently, a more potent anti-androgen, MDV3100 (enzalutamide, marketed as XTANDI® by Astellas Pharma US, Inc., Northbrook, Ill., and Medivation Inc., San Francisco, Calif.), has been discovered that lacks agonist activity. Tran et al. Science 324, 787-790 (2009). Based on convincing preclinical and clinical data, MDV3100 has been approved by the FDA for treatment of men with metastatic CRPC previously treated with docetaxel. On-going clinical trials are also testing MDV3100 as a monotherapy in patients with advanced prostate cancer who have not yet been castrated and as a neoadjuvant therapy in men diagnosed with prostate cancer but who have not yet undergone prostatectomy.
Although MDV3100 has shown tremendous efficacy in clinical trials, many who initially responded favorably have since developed resistance to this second generation anti-androgen. Kim et al. Current treatment options in oncology 13, 189-200 (2012).
There thus exists the need for novel compositions and methods for patient stratification and prediction of drug sensitivity for treatments for prostate cancer, breast cancer and other AR-related diseases. There also exists the need for novel therapies for AR-related diseases.